USP17L2

gene
On this page

Also known as DUB3

Summary

USP17L2 (ubiquitin specific peptidase 17 like family member 2, HGNC:34434) is a protein-coding gene on chromosome 8p23.1, encoding Ubiquitin carboxyl-terminal hydrolase 17 (Q6R6M4). Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.

Enables cysteine-type deubiquitinase activity. Involved in several processes, including CAAX-box protein processing; protein deubiquitination; and regulation of defense response. Located in endoplasmic reticulum membrane and nucleus.

Source: NCBI Gene 377630 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 1 total
  • Druggable target: yes
  • MANE Select transcript: NM_201402

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:34434
Approved symbolUSP17L2
Nameubiquitin specific peptidase 17 like family member 2
Location8p23.1
Locus typegene with protein product
StatusApproved
AliasesDUB3
Ensembl geneENSG00000223443
Ensembl biotypeprotein_coding
OMIM610186
Entrez377630

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000333796

RefSeq mRNA: 1 — MANE Select: NM_201402 NM_201402

CCDS: CCDS43713

Canonical transcript exons

ENST00000333796 — 1 exons

ExonStartEnd
ENSE000021995241213643512138849

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 84.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0228 / max 5.2550, expressed in 12 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter IDTPM avgSamples expressed
919040.022812

Top tissues by expression

99 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047384.66gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099177.19gold quality
corpus callosumUBERON:000233675.04gold quality
sural nerveUBERON:001548862.93gold quality
calcaneal tendonUBERON:000370154.92silver quality
primary visual cortexUBERON:000243652.64gold quality
stromal cell of endometriumCL:000225551.68silver quality
adrenal tissueUBERON:001830350.46silver quality
superior frontal gyrusUBERON:000266148.97gold quality
monocyteCL:000057647.29silver quality
leukocyteCL:000073847.17silver quality
colonic epitheliumUBERON:000039745.96gold quality
ventricular zoneUBERON:000305343.73gold quality
putamenUBERON:000187443.54gold quality
bone marrow cellCL:000209242.82gold quality
caudate nucleusUBERON:000187342.81gold quality
right frontal lobeUBERON:000281042.04gold quality
nucleus accumbensUBERON:000188241.56gold quality
tonsilUBERON:000237241.52gold quality
dorsolateral prefrontal cortexUBERON:000983441.51gold quality
Brodmann (1909) area 9UBERON:001354041.41silver quality
skeletal muscle tissueUBERON:000113440.31gold quality
brainUBERON:000095539.99gold quality
temporal lobeUBERON:000187139.78gold quality
left ovaryUBERON:000211939.75silver quality
amygdalaUBERON:000187639.47gold quality
anterior cingulate cortexUBERON:000983539.16silver quality
cerebral cortexUBERON:000095639.01gold quality
Ammon’s hornUBERON:000195438.54silver quality
hypothalamusUBERON:000189838.05silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no0.17

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 18)

  • human DUB-3, like the murine DUB family members, is transiently induced in response to cytokines and can, when constitutively expressed, block growth factor-dependent proliferation. (PMID:14699124)
  • Identifies DUB3 as being one of 30 genes with the most variable copy numbers in three human genomes. (PMID:19718026)
  • As a major regulator of Cdc25A, Dub3 is an example of a transforming ubiquitin hydrolase that subverts a key component of the cell cycle machinery, promoting oncogenic transformation. (PMID:20228808)
  • Recently, much progress has been made in understanding the physiological functions of cytokine-inducible DUBs such as DUB-1, DUB-2, and DUB-3/USP17, in regulation of cell proliferation and apoptosis in lymphocytes. [review] (PMID:23773437)
  • Dub3 counteracts H2AX E3 ligases RNF8 and RNF168. Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro. (PMID:24704006)
  • These data indicate that the Dub3 might be a valuable biomarker for the prediction of ovarian cancer prognosis and Dub3 inhibition might be a potential strategy for ovarian cancer treatment. (PMID:25776484)
  • In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome attributed to low expression of USP17. (PMID:26617781)
  • We provide evidence that DUB3 proteins regulate YAP/TAZ activity by controlling the stability of the E3 ligase ITCH, the LATS kinases and the AMOT family proteins. As a novel Hippo pathway regulator, DUB3 has the potential to act a tumor suppressor by limiting YAP activity. (PMID:28061504)
  • Dub3 is identified as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. (PMID:28198361)
  • these data identify DUB3 and USP7 as factors that regulate DNA replication by controlling Geminin protein stability, and suggest that USP7 may be involved in Geminin dysregulation during breast cancer progression. (PMID:28288134)
  • DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4. (PMID:30057199)
  • further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis (PMID:30628680)
  • our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer. (PMID:30718431)
  • DUB3 deubiquitinates and stabilizes NRF2 in chemotherapy resistance of colorectal cancer. (PMID:30778200)
  • DUB3 functions as a novel cyclin A regulator through maintaining cyclin A stability. (PMID:30935108)
  • NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3. (PMID:35927236)
  • USP17L2-SIRT7 axis regulates DNA damage repair and chemoresistance in breast cancer cells. (PMID:36040642)
  • Clinicopathological Significance of DUB3 Expression in Non-small Cell Lung Cancer and Relationship Between DUB3 Expression and LATS1 Expression. (PMID:37652526)

Cross-species orthologs

0 orthologs

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 17Q6R6M4 (reviewed: Q6R6M4)

Alternative names: Deubiquitinating enzyme 17-like protein 2, Deubiquitinating protein 3, Ubiquitin carboxyl-terminal hydrolase 17-like protein 2, Ubiquitin thioesterase 17-like protein 2, Ubiquitin-specific-processing protease 17-like protein 2

All UniProt accessions (1): Q6R6M4

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes. Regulates cell proliferation by deubiquitinating and inhibiting RCE1 thereby controlling the small GTPases NRAS and HRAS localization and activation. In parallel, mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression. Also regulates cell proliferation and apoptosis through deubiquitination of SUDS3 a regulator of histone deacetylation. Through activation of the Rho family GTPases RAC1A, CDC42 and RHOA, regulates cell migration. Through the cleavage of ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains of the cytoplasmic innate immune receptors RIGI and IFIH1 stimulates the cellular response to viral infection.

Subunit / interactions. Interacts with SUDS3; the interaction is direct.

Subcellular location. Nucleus. Endoplasmic reticulum.

Tissue specificity. Broadly expressed.

Induction. Up-regulated by IL4/interleukin-4, IL6/interleukin-6 and chemokines including CXCL8 and CXCL12 (at protein level). Up-regulated during the G1/S transition of the cell cycle.

Miscellaneous. Overexpressed in a subset of human breast cancers, overexpression leading to an abnormally high level of CDC25A, which arrests cells through replication stress or premature mitosis, the latter occurring when CDK1 is activated inappropriately.

Similarity. Belongs to the peptidase C19 family. USP17 subfamily.

RefSeq proteins (1): NP_958804* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001394Peptidase_C19_UCHDomain
IPR018200USP_CSConserved_site
IPR028889USPDomain
IPR038765Papain-like_cys_pep_sfHomologous_superfamily
IPR050164Peptidase_C19Family

Pfam: PF00443

UniProt features (26 total): sequence conflict 13, compositionally biased region 4, region of interest 3, active site 2, chain 1, domain 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q6R6M4-F167.790.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 334 (proton acceptor); 89 (nucleophile)

Mutagenesis-validated functional residues (1):

PositionPhenotype
89abolishes both enzymatic activity and effects on cell proliferation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

IDPathway
R-HSA-5689880Ub-specific processing proteases
R-HSA-9648002RAS processing

MSigDB gene sets: 138 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE

GO Biological Process (20): MAPK cascade (GO:0000165), apoptotic process (GO:0006915), negative regulation of protein processing (GO:0010955), protein deubiquitination (GO:0016579), regulation of cell migration (GO:0030334), regulation of protein stability (GO:0031647), negative regulation of GTPase activity (GO:0034260), regulation of cell population proliferation (GO:0042127), regulation of apoptotic process (GO:0042981), positive regulation of GTPase activity (GO:0043547), regulation of defense response to virus by host (GO:0050691), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), CAAX-box protein processing (GO:0071586), negative regulation of protein targeting to membrane (GO:0090315), regulation of G2/MI transition of meiotic cell cycle (GO:0110030), regulation of ruffle assembly (GO:1900027), positive regulation of MDA-5 signaling pathway (GO:1900245), positive regulation of RIG-I signaling pathway (GO:1900246), proteolysis (GO:0006508)

GO Molecular Function (5): cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-2 pathways:

CategoryPathways
Deubiquitination1
RAF/MAP kinase cascade1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein processing2
GTPase activity2
regulation of GTPase activity2
protein deubiquitination2
positive regulation of pattern recognition receptor signaling pathway2
positive regulation of intracellular signal transduction2
intracellular membrane-bounded organelle2
cytoplasm2
intracellular signaling cassette1
programmed cell death1
apoptotic signaling pathway1
execution phase of apoptosis1
negative regulation of proteolysis1
regulation of protein processing1
negative regulation of protein maturation1
cysteine-type deubiquitinase activity1
protein modification by small protein removal1
cell migration1
regulation of cell motility1
regulation of biological quality1
negative regulation of biological process1
negative regulation of hydrolase activity1
cell population proliferation1
regulation of cellular process1
apoptotic process1
regulation of programmed cell death1
positive regulation of hydrolase activity1
regulation of defense response to virus1
CAAX-box protein maturation1
protein targeting to membrane1
negative regulation of cellular process1
regulation of protein targeting to membrane1
negative regulation of establishment of protein localization1
G2/MI transition of meiotic cell cycle1
regulation of meiotic cell cycle phase transition1
regulation of cell cycle G2/M phase transition1
ruffle assembly1
regulation of plasma membrane bounded cell projection assembly1
positive regulation of immune effector process1
MDA-5 signaling pathway1

Protein interactions and networks

STRING

528 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
USP17L2ZUP1Q96AP4912
USP17L2SNAI1O95863623
USP17L2USP13Q92995604
USP17L2USP37Q86T82592
USP17L2JOSD1Q15040591
USP17L2RCE1Q9Y256560
USP17L2FBXL14Q8N1E6546
USP17L2USP28Q96RU2545
USP17L2OTUD5Q96G74533
USP17L2CDK4P11802533
USP17L2JOSD2Q8TAC2528
USP17L2OTUB1Q96FW1521
USP17L2AMOTQ4VCS5520
USP17L2USP26Q9BXU7519
USP17L2USP25Q9UHP3515

IntAct

3 interactions, top by confidence:

ABTypeScore
USP17L24USP17L7psi-mi:“MI:0914”(association)0.350
USP17L2USP17L7psi-mi:“MI:0914”(association)0.350

BioGRID (130): LGMN (Biochemical Activity), USP17L2 (Co-fractionation), USP17L2 (Affinity Capture-Western), USP17L2 (Affinity Capture-Western), SUDS3 (Reconstituted Complex), SUDS3 (Affinity Capture-Western), SUDS3 (Affinity Capture-MS), USP17L2 (Affinity Capture-Western), HDAC2 (Affinity Capture-Western), USP17L2 (Affinity Capture-Western), IL33 (Affinity Capture-Western), USP17L2 (Affinity Capture-Western), SNAI1 (Affinity Capture-Western), SNAI1 (Reconstituted Complex), USP17L2 (Reconstituted Complex)

ESM2 similar proteins: A2A5N8, A6NCW0, A6NCW7, A8MUK1, B1AQJ2, B2RQC2, C9J2P7, C9JJH3, C9JLJ4, C9JPN9, C9JVI0, D3ZWK4, D6R901, D6R9N7, D6RA61, D6RBM5, D6RBQ6, D6RCP7, D6RJB6, E9Q9U0, G5E8G2, G5E8I7, O94966, P0C7H9, P0C7I0, P35125, P51784, Q0E2F9, Q0WX57, Q2TAC6, Q3UJD6, Q4KLL9, Q5R7G8, Q5TKR9, Q61068, Q66HE5, Q6J1Y9, Q6PFD6, Q6QN14, Q6R6M4

Diamond homologs: A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6NNY8, A6QNM7, A7Z056, B1AY13, B1WBD7, D2HBJ8, D6RBM5, E1C213, E7F6T8, E9Q9U0, F6Z5C0, F8VPU6, F8VPZ3, M9PD06, O00507, O22207, O60079, O74442, O94269, O94966, O96612, P0C7I0, P0C8Z3, P0CAQ1, P35125, P39538, P40453, P51784, P53874, P55824, P70398, Q01988, Q09738, Q0V9G5, Q28CN3, Q2HJE4

SIGNOR signaling

2 interactions.

AEffectBMechanism
USP17L2“down-regulates quantity by destabilization”LGMNdeubiquitination
USP17L2“up-regulates quantity by stabilization”BHLHE40deubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance0
Likely benign1
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

46 predictions. Top by Δscore:

VariantEffectΔscore
8:12137469:T:TAdonor_gain0.3800
8:12138645:T:TGacceptor_gain0.3700
8:12137984:C:Gacceptor_gain0.3500
8:12137483:TTCC:Tdonor_gain0.3000
8:12137543:T:Adonor_gain0.3000
8:12137386:GGGTA:Gdonor_loss0.2900
8:12137387:GGTA:Gdonor_loss0.2900
8:12137388:GTAC:Gdonor_loss0.2900
8:12137389:TA:Tdonor_loss0.2900
8:12137390:A:Cdonor_loss0.2900
8:12137391:C:Tdonor_loss0.2900
8:12137392:CTTCG:Cdonor_loss0.2800
8:12137643:A:Cacceptor_gain0.2800
8:12138731:ACCTC:Adonor_gain0.2800
8:12138732:CCTCC:Cdonor_gain0.2800
8:12137385:AGGGT:Adonor_loss0.2700
8:12137639:C:CCacceptor_gain0.2700
8:12137375:G:Cdonor_gain0.2600
8:12137643:A:ACacceptor_gain0.2600
8:12138725:CCACT:Cdonor_loss0.2600
8:12138726:CACTC:Cdonor_loss0.2600
8:12138727:ACTCA:Adonor_loss0.2600
8:12138728:CT:Cdonor_loss0.2600
8:12138729:T:TAdonor_loss0.2600
8:12138730:CACCT:Cdonor_loss0.2600
8:12138731:AC:Adonor_loss0.2600
8:12138732:C:Tdonor_loss0.2600
8:12138732:CCT:Cdonor_gain0.2600
8:12137634:CTCTT:Cacceptor_gain0.2500
8:12138624:T:TGacceptor_gain0.2400

AlphaMissense

3495 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
8:12137973:G:TA263D0.988
8:12137966:C:AK265N0.987
8:12137966:C:GK265N0.987
8:12138142:A:GC207R0.980
8:12137912:G:CF283L0.979
8:12137912:G:TF283L0.979
8:12137914:A:GF283L0.979
8:12138154:A:GS203P0.977
8:12138024:A:GL246P0.970
8:12138147:A:GI205T0.969
8:12138147:A:CI205S0.967
8:12138141:C:GC207S0.965
8:12138142:A:TC207S0.965
8:12137968:T:CK265E0.961
8:12138000:C:TC254Y0.961
8:12138024:A:TL246H0.961
8:12138121:A:GS214P0.961
8:12138140:A:CC207W0.961
8:12138133:A:GC210R0.960
8:12138001:A:GC254R0.958
8:12138131:G:CC210W0.958
8:12138132:C:GC210S0.958
8:12138133:A:TC210S0.958
8:12138132:C:TC210Y0.957
8:12138150:T:GQ204P0.955
8:12138160:A:GW201R0.955
8:12138160:A:TW201R0.955
8:12138000:C:GC254S0.954
8:12138001:A:TC254S0.954
8:12137974:C:GA263P0.953

dbSNP variants (sampled 300 via entrez): RS1008742680 (8:12140222 C>G,T), RS10090565 (8:12140019 G>A), RS10090570 (8:12140021 G>A), RS1012872703 (8:12139518 G>A), RS1017747908 (8:12136364 A>T), RS1022360289 (8:12138011 A>G), RS1030536033 (8:12136194 G>A), RS1031036734 (8:12138781 C>G), RS1031066170 (8:12140187 T>C), RS1035318720 (8:12138552 A>C,G), RS1038820269 (8:12137439 TGGG>T,TGG,TGGGG), RS1039095503 (8:12138452 G>C,T), RS1042709438 (8:12135947 T>C), RS1042853860 (8:12137345 C>G,T), RS1043714759 (8:12139659 A>G)

Disease associations

OMIM: gene MIM:610186 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3739248 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

ChemicalActions (top 5)PubMed papers
sodium arseniteincreases expression1
butyraldehydeincreases expression1
abrineincreases expression1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)increases expression1
Acetaminophenincreases expression1
Air Pollutantsincreases expression1
Benzo(a)pyrenedecreases methylation1
Cadmiumdecreases expression1
Rifampindecreases expression1
Thiramincreases expression1
Valproic Acidincreases methylation1
Lactic Aciddecreases expression1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL3744223BindingInhibition of USP17 in human HEK293T cells using fluorogenic substrate ub-rhodamine110 preincubated for 30 mins followed by substrate addition measured every 4 mins for 1 hr by microplate reader analysisDevelopment of a potent and selective cell penetrant Legumain inhibitor. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.